Potent mouse germline mutagenesis by ethylnitrosourea (ENU) is being combined with efficient breeding and screening protocols to generate an extended series of viable mouse mutants deficient in phenylalanine clearance. These hyperphenylalanemic (HPH) mutants will be characterized genetically and biochemically to assign each distinct lesion to a genetic locus and a step in phenylalanine catabolism. With lesions of particular interest, locus-specific mutant isolation methods will then be employed to obtain an extended series of mutant alleles, including lesions that may be lethal to development when homozygous. The development consequences of HPH will be investigated in two different situations-the exposure of genetically-affected neonates to high level of phenylalanine; and the exposure of mutant females to phenylalanine during pregnancy. The embryological investigations involved in these studies will be carried out collaboratively with Dr. Susan Lewis (Research Triangle Park, North Carolina). We are making these mouse mutant models available to laboratories that specialize in the biochemical analysis of mammalian PKU. A number of biological and biomedical investigations become possible, given the salient mutant lines.